Author Information

Atherosclerotic cardiovascular disease, including myocardial infarction and stroke, remains the most common cause of death and disability in the developed world. The primary driver for development of the disease is inflammation (1); in atherosclerosis, this is primarily due to macrophage infiltration of the vascular intima. Positron emission tomography (PET) imaging with the metabolic tracer 18F-fluorodeoxyglucose (18F-FDG) is a highly sensitive, noninvasive technique that can give a readout of vascular glucose metabolism, believed to be a surrogate of atherosclerotic plaque inflammation (2). Glucose uptake by macrophages is significantly higher than in other plaque cells (3,4). Macrophages can also metabolize fatty acids, but in the anaerobic environment of the plaque, they preferentially use glucose because this does not require oxygen to produce adenosine triphosphate (5,6). Studies in humans with atherosclerosis have demonstrated that the degree of vascular 18F-FDG uptake relates to the presence of recent plaque destabilization (7,8), cardiovascular risk factors (9,10), and high-risk plaque morphology (11). It has also been possible to test the efficacy of antiatherosclerotic drugs (12) by measuring the changes that they cause to the 18F-FDG signal. Pre-clinical studies in animal models of atherosclerosis (without diabetes) have largely confirmed that the basis of the signal is inflammation (13), but not consistently so (14). This is not surprising when we consider that all cells metabolizing glucose accumulate 18F-FDG. Plaque 18F-FDG uptake in nondiabetic individuals is therefore a useful marker of enhanced glucose metabolism, correlating with inflammation, but not specific for it (15). Hypoxia also seems to increase the degree to which inflammatory cells accumulate 18F-FDG (16).

The noninvasive readout of inflammation in patients with type 2 diabetes mellitus (DM2) is especially attractive because they are at higher risk of vascular events than those without DM2. DM2 is a complex disease. Although its hallmark is hyperglycemia and impaired glucose metabolism, equally important are disturbances in lipid metabolism. Both glucose and lipid levels in plasma can still be normal in early forms of DM2, even when the metabolism of glucose and lipid is already severely impaired. This becomes obvious only when studied by either dynamic testing (for example, by a glucose tolerance or lipid clearance test) or, better yet, through flux studies using metabolic tracers. The second core feature of DM2 is insulin resistance, defined as the inability of insulin to regulate glucose and lipid metabolism. Insulin is the principal regulator of glucose and lipid metabolism, and therefore disturbances in glucose and lipid metabolism are intimately linked with insulin resistance in DM2. With the drugs that we have at our disposal, it is easier to correct hyperglycemia than to improve insulin resistance. It is therefore of fundamental importance to differentiate the effects of hyperglycemia (i.e., glucose toxicity) from the role of insulin resistance in atherosclerosis.

With regard to atherosclerosis, the question remains whether PET imaging with 18F-FDG can accurately detect plaque inflammation in subjects with DM2 or animal models of DM2. It is also unclear how insulin resistance per se affects 18F-FDG uptake in macrophages, cells that do express the insulin receptor (17), but not the insulin responsive GLUT4 glucose transporter (18). It is also important to remember that because 18F-FDG is a glucose analog whose uptake is competitively inhibited by increasing blood glucose concentration (19,20), it is unknown whether vascular 18F-FDG uptake is affected by hyperglycemia at the time of imaging.

The only study to explore these questions, at least in humans, was undertaken by Kim et al. (21), who demonstrated increasing levels of 18F-FDG uptake within the carotid arteries of control subjects, through those with impaired glucose tolerance to frank DM2. Because the uptake of 18F-FDG into cells is competitive with glucose, the authors were careful to ensure that the fasting glucose level at the time of imaging was within normal limits. Although this study is encouraging, the ability to perform 18F-FDG PET imaging in an animal model of DM2, where the underlying pathology can be probed in a controlled way, has not been tested.

In this issue of iJACC, Silvola et al. (22) investigated the effect of mouse age and the duration of high-fat diet on 18F-FDG uptake in 2 models of murine atherosclerosis and compared with controls. The novelty of this work is the use of a mouse model in which insulin-like growth factor II (IGF-II) is overexpressed in beta cells using the rat insulin promoter on a LDLR−/−ApoB100/100 background. LDLR−/−ApoB100/100 mice are the “nondiabetic” controls, a strain that is commonly used to model human atherosclerosis in mice. The authors had shown in a previous study that IGF-II/LDLR−/−ApoB100/100 mice are characterized by glucose intolerance, increased fasting glycemia, and insulin resistance when compared with LDLR−/−ApoB100/100 mice (23). This mimics early DM2, but it is also important to point out that these mice do not differ much in terms of hyperglycemia from controls when fed the same diet. Why these mice are insulin resistant remains somewhat unclear. Insulin resistance is primarily due to a failure of insulin to suppress hepatic glucose production and/or to increase glucose uptake into muscle and adipose tissue. In the IGF-II/LDLR−/−ApoB100/100 mice, it may be that initial oversecretion of insulin from beta cells generates chronic hyperinsulinemia that begets insulin action. An alternative explanation for the insulin-resistant phenotype may lie in the experimental approach chosen to overexpress IGF2, which is under the control of the rat insulin promoter. It has been realized in recent years that the rat insulin promoter is not only turned on in beta cells, but also in the hypothalamus where insulin is expressed during development (24). Hypothalamic overexpression of IGF-II may impair hypothalamic control of whole-body insulin action through autonomic dysregulation that can lead to systemic insulin resistance. Although this model may appear somewhat obscure, hyperinsulinemia (25) and hypothalamic dysfunction (26) are now believed to play important roles in the pathogenesis of DM2 in humans, and therefore this model is clinically relevant.

Probably the 2 most important factors contributing to DM2 in humans are excessive caloric intake and aging. Both represent metabolic stressors that worsen insulin resistance and unveil a diabetic phenotype, which is true in humans and rodents.

Thus, the authors examined the impact of high-fat feeding and aging on plaque size, macrophage density, and uptake of 18F-FDG. They found no differences between the 2 models regarding plaque development and cellular composition, despite the development of diabetes by a high-fat diet. They demonstrated that the “sweet spot” for using 18F-FDG PET to image vascular inflammation in both models was found in mice at least 6 months old and after 3 to 4 months of high-fat feeding. Interestingly, aging decreased plaque macrophage density (previously demonstrated by Rong et al. [27] in apoE−/− mice), although plaque size itself increased and calcification was predominant with subsequent low 18F-FDG signal, which is likely due to impaired macrophage function and metabolism in aging.

There are several limitations of the current study. Although lipid levels of IGF-II/LDLR−/−ApoB100/100 mice did not differ from LDLR−/−ApoB100/100 controls, as pointed out previously, this does not mean that lipid metabolism is not altered in these mice and thus the role of altered lipid flux on 18F-FDG uptake remains unclear. Further, the authors did not examine the impact of hyperglycemia on 18F-FDG uptake because the 2 mice models did not, at least clinically significantly, differ in terms of glycemia when fed the same diet. Another issue is that females and males were not matched between groups. Sex has a marked effect on high-fat feeding–induced insulin resistance and metabolic derangement. For example, the IGF-II/LDLR−/−ApoB100/100 mice were predominantly females while the controls were mostly males which introduces a significant bias because females are often protected from high-fat feeding–induced insulin resistance (28).

Nevertheless, the current study represents an important first step in validating 18F-FDG PET imaging for the study of atherosclerosis in models of DM2. Ultimately, studies like these will allow us to dissect the role of specific components of DM2, such as glucose and lipid toxicity versus insulin resistance, as contributors to the increased cardiovascular risk in diabetes and the metabolic syndrome.

Footnotes

Dr. Buettner is supported in part by NIHDK0836558, Dr. Rudd by the NIHR Cambridge Biomedical Research Centre, and Dr. Fayad is supported in part by NIH/NHLBIR01 HL071021 and R01 HL078667. All authors have reported that they have no relationships relevant to the contents of this paper to disclose.

↵⁎ Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology.